The long term goal of the project is to gain a greater understanding of the function of cholecystokinin (CCK) neurons in the striatum. To this end the project is designed to provide basic information on the anatomy and biosynthesis of CCK neurons in the caudate nucleus. In addition, the interaction of CCK neurons with other known neurotransmitters in the caudate will be investigated. The basic information derived from these studies is vital to an understanding of the functional role of CCK in the striatum and it may enhance our knowledge of the pathophysiology of neurological disorders such as Huntington's disease and Parkinson's disease. This information may ultimately allow us to treat these disorders by selectively regulating the activity of CCK neurons and thus shift the balance between CCK and other neurotransmitters in the striatum. The specific aims of the proposed research are: 1) The cells or origin of the CCK in the caudate nucleus will be precisely defined using horseradish peroxidase retrograde tracing, CCK immunohistochemistry, lesion techniques and the CCK radioimmunoassay. 2) The in vivo biosynthesis of CCK in the striatum will be studied by stereotaxic injection of 35S methionine adjacent to the CCK cells which project to the striatum. Biosynthetically labeled CCK peptides removed from the striatum will be characterized by immunochemical techniques, HPLC chromatography, and conventional biochemical techniques. Their rate of synthesis, interconversion, and degradation will be measured. Experiments will be performed to begin to identify factors that regulate the rate of CCK biosynthesis and turnover. 3) The interaction of CCK with other striatal substances will be determined. In particular, the effect of CCK on the release of acetylcholine, dopamine, and GABA will be determined in vitro in striatal slices. The effect of CCK on endogenous dopamine release will be determined in the same preparation, dopamine will be quantitated by HPLC with electrochemical detection. Any consistent in vitro effects will be examined further in vivo with a push/pull cannula system. In addition, the effect of acetylcholine, dopamine and other dopamine agonists, GABA, substance P, enkephalin, and VIP on CCK will be determined in vitro from striatal slices. The released CCK will be quantitated with the CCK RIA.